Certain azacycloalkyl imidazopyrimidines; a new class of GABA brain receptor ligands

ABSTRACT

The invention encompasses compounds of the formula: ##STR1## and the pharmaceutically acceptable non-toxic salts thereof wherein n is 0, 1, or 2, X is ##STR2## Z is H 2 , oxygen or sulfur, and R 1 , R 2 , R 3 , R 4 , T, W, and Y are defined variables. 
     These compounds are highly selective agonists or inverse agonists for the GABAa brain receptors and are useful in the diagnosis and treatment of anxiety, sleep, and seizure disorders, overdose with benzodiazepine type drugs, and enhancement of alertness.

This application is a continuation-in-part of application pending U.S.patent application Ser. No. 07/557,577, filed Jun. 24, 1990 now U.S.Pat. No. 5,095,015.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain azacycloalkyl imidazopyrimidines whichselectively bind to GABAa receptors. This invention also relates topharmaceutical compositions comprising such compounds. It furtherrelates to the use of such compounds in treating anxiety, sleep andseizure disorders, and overdoses of benzodiazepine-type drugs, andenhancing alertness. The interaction of those compounds with a GABAbinding site, the benzodiazepine (BDZ) receptor, is described. Thisinteraction results in the pharmacological activities of thesecompounds.

2. Description of the Related Art

γ-Aminobutyric acid (GABA) is regarded as one of the major inhibitoryamino acid transmitters in the mammalian brain. Over 30 years haveelapsed since its presence in the brain was demonstrated (Roberts &Frankel, J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187:65-69, 1950). Since that time, an enormous amount of effort has beendevoted to implicating GABA in the etiology of seizure disorders, sleep,anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8:21-44, 1985). Widely, although unequally, distributed through themammalian brain, GABA is said to be a transmitter at approximately 30%of the synapses in the brain. In most regions of the brain, GABA isassociated with local inhibitory neurons and only in two regions is GABAassociated with longer projections. GABA mediates many of its actionsthrough a complex of proteins localized both on cell bodies and nerveendings: these are called GABAa receptors. Postsynaptic responses toGABA are mediated through alterations in chloride conductance thatgenerally, although not invariably, lead to hyperpolarization of thecell. Recent investigations have indicated that the complex of proteinsassociated with postsynaptic GABA responses is a major site of actionfor a number of structurally unrelated compounds capable of modifyingpostsynaptic responses to GABA. Depending on the mode of interaction,these compounds are capable of producing a spectrum of activities(either sedative, anxiolytic, and anticonvulsant, or wakefulness,seizures, and anxiety).

1,4-Benzodiazepines continue to be among the most widely used drugs inthe world. Principal among the benzodiazepines marketed arechlordiazepoxide, diazeparn, flurazepam, and triazolam. These compoundsare widely used as anxiolytics, sedative-hypnotics, muscle relaxants,and anticonvulsants. A number of these compounds are extremely potentdrugs; such potency indicates a site of action with a high affinity andspecificity for individual receptors. Early electrophysiological studiesindicated that a major action of benzodiazepines was enhancement ofGABAergic inhibition. The benzodiazepines were capable of enhancingpresynaptic inhibition of a monosynaptic ventral root reflex, aGABA-mediated event (Schmidt et al., 1967, Arch. Exp. Path. Pharmakol.258: 69-82). All subsequent electrophysiological studies (reviewed inTallman et al. 1980, Science 207: 274-81, Haefley et al., 1981, Handb.Exptl. Pharmacol. 33: 95-102) have generally confirmed this finding, andby the mid-1970s, there was a general consensus amongelectrophysiologists that the benzodiazepines could enhance the actionsof GABA.

With the discovery of the "receptor" for the benzodiazepines and thesubsequent definition of the nature of the interaction between GABA andthe benzodiazepines, it appears that the behaviorally importantinteractions of the benzodiazepines with different neurotransminersystems are due in a large part to the enhanced ability of GABA itselfto modify these systems. Each modified system, in turn, may beassociated with the expression of a behavior.

Studies on the mechanistic nature of these interactions depended on thedemonstration of a high-affinity benzodiazepine binding site (receptor).Such a receptor is present in the CNS of all vertebratesphylogenetically newer than the boney fishes (Squires & Braestrup 1977,Nature 166: 732-34, Mohler & Okada, 1977, Science, 198: 854-51, Mohler &Okada, 1977, Br. J. Psychiatry 133: 261-68). By using tritiateddiazepam, and a variety of other compounds, it has been demonstratedthat these benzodiazepine binding sites fulfill many of the criteria ofpharmacological receptors; binding to these sites in vitro is rapid,reversible, stereospecific, and saturable. More importantly, highlysignificant correlations have been shown between the ability ofbenzodiazepines to displace diazepam from its binding site and activityin a number of animal behavioral tests predictive of benzodiazepinepotency (Braestrup & Squires 1978, Br. J. Psychiatry 133: 249-60, Mohler& Okada, 1977, Science 198: 854-51, Mohler & Okada, 1977, Br. J.Psychiatry 133: 261-68). The average therapeutic doses of these drugs inman also correlate with receptor potency (Tallman et al. 1980, Science207: 274-281.).

In 1978, it became clear that GABA and related analogs could interact atthe low affinity (1 μM) GABA binding site to enhance the binding ofbenzodiazepines to the clonazepan-sensitive site (Tallman et al. 1978,Nature, 274: 383-85). This enhancement was caused by an increase in theaffinity of the benzodiazepine binding site due to occupancy of the GABAsite. The data were interpreted to mean that both GABA andbenzodiazepine sites were allosterically linked in the membrane as partof a complex of proteins. For a number of GABA analogs, the ability toenhance diazepam binding by 50% of maximum and the ability to inhibitthe binding of GABA to brain membranes by 50% could be directlycorrelated. Enhancement of benzodiazepine binding by GABA agonists isblocked by the GABA receptor antagonist (+) bicuculline; thestereoisomer (-) bicuculline is much less active (Tallman et al., 1978,Nature, 274: 383-85).

Soon after the discovery of high affinity binding sites for thebenzodiazepines, it was discovered that a triazolopyridazine couldinteract with benzodiazepine receptors in a number of regions of thebrain in a manner consistent with receptor heterogeneity or negativecooperativity. In these studies. Hill coefficients significantly lessthan one were observed in a number of brain regions, including cortex,hippocampus, and striatum. In cerebellum, triazolopyridazine interactedwith benzodiazepine sites with a Hill coefficient of 1 (Squires et al.,1979, Pharma. Biochem. Behav. 10: 825-30, Klepner et al. 1979,Pharmacol. Biochem. Behav. 11: 457-62). Thus, multiple benzodiazepinereceptors were predicted in the cortex, hippocampus, striatum, but notin the cerebellum.

Based on these studies, extensive receptor autoradiographic localizationstudies were carried out at a light microscopic level. Although receptorheterogeneity has been demonstrated (Young & Kuhar 1980, J. Pharmacol.Exp. Ther. 212: 337-46, Young et al., 1981 J. Pharmacol Exp. ther 216:425-430, Niehoff et al. 1982, J. Pharmacol. Exp. Ther. 221: 670-75), nosimple correlation between localization of receptor subtypes and thebehaviors associated with the region has emerged from the early studies.In addition, in the cerebellum, where one receptor was predicted frombinding studies, autoradiography revealed heterogeneity of receptors(Niehoff et al., 1982, J. Pharmacol. Exp. Ther. 221: 670-75).

A physical basis for the differences in drug specificity for the twoapparent subtypes of benzodiazepine sites has been demonstrated bySieghart & Karobath, 1980, Nature 286: 285-87. Using gel electrophoresisin the presence of sodium dodecyl sulfate, the presence of severalmolecular weight receptors for the benzodiazepines has been reported.The receptors were identified by the covalent incorporation ofradioactive flunitrazepam, a benzodiazepine which can covalently labelall receptor types. The major labeled bands have moelcular weights of50,000 to 53,000, 55,000, and 57,000 and the triazolopyridazines inhibitlabeling of the slightly higher molecular weight forms (53,000, 55,000,57,000) (Seighart et al. 1983, Eur. J. Pharmacol. 88: 291-99).

At that time, the possibility was raised that the multiple forms of thereceptor represent "isoreceptors" or multiple allelic forms of thereceptor (Tallman & Gallager 1985, Ann. Rev. Neurosci. 8, 21-44).Although common for enzymes, genetically distinct forms of receptorshave not generally been described. As we begin to study receptors usingspecific radioactive probes and electrophoretic techniques, it is almostcertain that isoreceptors will emerge as important in investigations ofthe etiology of psychiatric disorders in people.

The GABAa receptor subunits have been cloned from bovine and human cDNAlibraries (Schoenfield et al., 1988; Duman et al., 1989). A number ofdistinct cDNAs were identified as subunits of the GABAa receptor complexby cloning and expression. These are categorized into ∝, β, γ, δ, ε, andprovide a molecular basis for the GABAa receptor heterogeneity anddistinctive regional pharmacology (Shivvers et al., 1980; Levitan etal., 1989). The γ subunit appears to enable drugs like benzodiazepinesto modify the GABA responses (Pritchett et al., 1989). The presence oflow Hill coefficients in the binding of ligands to the GABAa receptorindicates unique profiles of subtype specific pharmacological action.

Drugs that interact at the GABAa receptor can possess a spectrum ofpharmacological activities depending on their abilities to modify theactions of GABA. For example, the beta-carbolines were first isolatedbased upon their ability to inhibit competitively the binding ofdiazepam to its binding site (Nielsen et al., 1979, Life Sci. 25:679-86). The receptor binding assay is not totally predictive about thebiological activity of such compounds; agonists, partial agonists,inverse agonists, and antagonists can inhibit binding. When thebeta-carboline structure was determined, it was possible to synthesize anumber of analogs and test these compounds behaviorally. It wasimmediately realized that the beta-carbolines could antagonize theactions of diazepam behaviorally (Tenen & Hirsch, 1980, Nature 288:609-10). In addition to this antagonism, beta-carbolines possessintrinsic activity of their own opposite to that of the benzodiazepines;they become known as inverse agonists.

In addition, a number of other specific antagonists of thebenzodiazepine receptor were developed based on their ability to inhibitthe binding of benzodiazepines. The best studied of these compounds isan imidazodiazepine, (Hunkelef et al., 1981, Nature 290: 514-516). Thiscompound is a high affinity competitive inhibitor of benzodiazepine andbeta-carboline binding and is capable of blocking the pharmacologicalactions of both these classes of compounds. By itself, it possesseslittle intrinsic pharmacological activity in animals and humans(Hunkeler et al., 1981, Nature 290: 514-16; Darragh et al., 1983, Eur.J. Clin. Pharmacol. 14: 569-70). When a radiolabeled form of thiscompound was studied (Mohler & Richards, 1981, Nature 294: 763-65), itwas demonstrated that this compound would interact with the same numberof sites as the benzodiazepines and beta-carbolines, and that theinteractions of these compounds were purely competitive. This compoundis the ligand of choice for binding to GABAa receptors because it doesnot possess receptor subtype specificity and measures each state of thereceptor.

The study of the interactions of a wide variety of compounds similar tothe above has led to the categorizing of these compounds. Presently,those compounds possessing activity similar to the benzodiazepines arecalled agonists. Compounds possessing activity opposite tobenzodiazepines are called inverse agonists, and the compounds blockingboth types of activity have been termed antagonists. This categorizationhas been developed to emphasize the fact that a wide variety ofcompounds can produce a spectrum of pharmacological effects, to indicatethat compounds can interact at the same receptor to produce oppositeeffects, and to indicate that beta-carbolines and antagonists withintrinsic anxiogenic effects are not synonymous.

A biochemical test for the pharmacological and behavioral properties ofcompounds that interact with the benzodiazepine receptor continues toemphasize the interaction with the GABAergic system. In contrast to thebenzodiazepines, which show an increase in their affinity due to GABA(Tallman et al., 1978, Nature 274: 383-85, Tallman et al., 1980, Science207: 274-81), compounds with antagonist properties show little GABAshift (i.e., change in receptor affinity due to GABA) (Mohler & Richards1981, Nature 294: 763-65), and the inverse agonists actually show adecrease in affinity due to GABA [(Braestrup & Nielson 1981, Nature 294:472-474)]. Thus, the GABA shift predicts generally the expectedbehavioral properties of the compounds.

Various compounds have been prepared as benzodiazepine agonists andantagonists. For example, U.S. Pat. Nos. 4,713,383, and 4,643,999 andEur. Patent Applications Nos. 181,282, 219,748 and 263,071 teach variousbenzodiazpine agonists and antagonists useful in the treatment ofanxiety.

U.S. Pat. No. 4,643,999 discloses compounds of the formula: ##STR3##wherein R is an aryl of 6 to 12 carbon atoms, R₁ is selected from thegroup consisting of hydrogen and alkyl, alkoxy and alkylthio of 1 to 5carbon atoms when R₂ and R₃ together form a carbon-nitrogen bond or R₁and R₂ together are =0 when R₃ is selected from the group consisting ofhydrogen, alkyl of 1 to 5 carbon atoms and alkenyl of 2 to 5 carbonatoms, R₄ is selected from the group consisting of alkoxy and alkylthioof 1 to 5 carbon atoms, R₅ is selected from the group consisting ofhydrogen and alkyl of 1 to 5 carbon atoms, and their non-toxic,pharmaceutically acceptable acid addition salts.

U.S. Pat. No. 4,713,383 teaches compounds of the formula: ##STR4##wherein R₁ =(un)substituted Ph, (dihydro)furanyl, tetrahydrofuranyl,(dihydro)thienyl, tetrahydrothienyl, pyranyl, ribofuranosyl, allC-attached;

R₂ =H, alkyl; X=O, S, R₃ N; R₃ =H, alkenyl, alkynyl, C₃₋₂₀ cycloalkyl,(un)substituted alkyl, aryl, aralkyl, where aryl is Ph, pyridinyl,thienyl, furanyl; ring A may be substituted by alkyl, alkoxy, halo,amino, alkylthio, etc.

European Patent Application EP 181,282 discloses compounds of theformula: ##STR5## wherein

R₁ =(substituted) Ph or heterocycle;

R₂ =H, alkyl, alkenyl, hydroxyalkyl, aralkyl, aralkenyl, aryl; R₃ =H,alkyl, alkoxy, HO, halo, F₃ C, O₃ N, H₂ N, alkylthio, alkylsulfinyl,alkylsulfonyl, aralkoxy; X=O, S, NR₄ ;

R₄ =H, alkyl, aralkyl, cycloalkyl, alkenyl, alkynyl, aryl, (substituted)aminoaklyl, hydroxyalkyl.

European Patent Application EP 217,748 teaches compounds of the formula:##STR6## wherein A=atoms to complete a fused. (un)substituted,(un)saturated, carbocyclic or heterocyclic ring comprising C, O, N, andS; X=O, S, RN; R=H, OH, hydroxyalkyl, aryl, H₂ NC(:NH), alkyl, alkenyl,alkynyl, optionally with hetero atom interrupters; R=(un)substitutedcarbocyclyl, heterocyclyl; R₂ =(un)substituted Ph.

European Patent Application EP 263,071 discloses compounds of theformula ##STR7## wherein X=O, NR, S:

R=H, lower alkyl, alkenyl, alkynyl;

R₁ =(substituted) Ph, furyl, thienyl, pyridyl, pyrrolyl, etc; ringA=C₅₋₈ cycloalkene, heterocycle, etc., each ring A being unsubstitutedor substituted by lower alkyl, alkoxy, OH, halogen, CF₃, NO₂, carbamoyl,carbamoylalkyl, etc.

These compounds differ from the compounds of the present invention. U.S.Pat. No. 4,713,383, and European Patent Applications Nos. 181,282,217,748 and 263,071 each teach carbocyclic compounds having anadditional nitrogen atom in the carbocyclic system. U.S. Pat. No.4,643,999 teaches imidazopyrimidines lacking the aryl substituents atposition 2, the nitrogen in the ring system at position 9, and othervarious ring substituents of the compounds of the present invention.

SUMMARY OF THE INVENTION

This invention provides novel compounds of the general Formula I whichinteract with a modulatory site on one or more subtypes of the brainGABAa receptor and possess intrinsic activites ranging from agonist toinverse agonist.

The invention provides pharmaceutical compositions comprising compoundsof Formula I. The invention also provides compounds useful in enhancingalertness, treatment of seizure, anxiety, and sleep disorders, andtreatment of benzodiazepine overdoses. Accordingly, a broad embodimentof the invention is directed to compounds of Formula I. ##STR8## and thepharmaceutically acceptable non-toxic salts thereof wherein

Z is H₂, oxygen or sulfur;

R₁ and R₂ are hydrogen or straight chain or branched lower alkyl having1-6 carbon atoms;

X is ##STR9## with the proviso that when X is ##STR10## T is oxygen orsulfur, and when X is ##STR11## R₃ is hydrogen, halogen, aryloxy, alkoxyhaving 1-6 carbon atoms or OCOR₅ where R₅ is hydrogen, straight orbranched chain alkyl having 1-6 carbon atoms, alkoxy having 1-6 carbonatoms, or dialkylamino where each alkyl has 1-6 carbon atoms, and R₄ isH, lower alkyl having 1-6 carbon atoms or COR₆ where R₆ is hydrogen,straight or branched chain alkyl having 1-6 carbon atoms, alkoxy having1-6 carbon atoms or dialkylamino where each alkyl has 1-6 carbon atoms;

W is phenyl, 2- or 3-thienyl or 2-, 3-, or 4-pyridyl; or phenyl, 2- or3-thienyl or 2-, 3-, or 4-pyridyl, each of which is mono ordisubstituted with halogen, lower alkyl, or straight or branched chainlower alkoxy having 1-6 carbon atoms;

Y is

i) hydrogen, phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or4(5)-imidazolyl, 2-pyrimidinyl, or 1-indanyl;

ii) phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 4(5)-imidazolyl,or 2-pyrimidinyl, each of which is mono or disubstituted with halogen,lower alkyl having 1-6 carbon atoms, lower alkoxy having 1-6 carbonatoms, or alkoxylalkyl where the alkoxy portion is straight or branchedchain alkoxy having 1-6 carbon atoms and the alkyl portion is straightor branched chain alkyl having 1-6 carbon atoms;

iii) straight or branched chain alkyl having 1-6 carbon atoms;

iv) straight or branched chain alkyl having 1-6 carbon atoms, whereineach alkyl is substituted with the groups of ii;

v) cycloalkyl having 3-10 carbon atoms, cycloalkyl alkyl where thecycloalkyl portion has 3-7 carbon atoms and the alkyl portion has 1-6carbon atoms;

vi) aminoalkyl where the alkyl portion is straight or branched chainalkyl having 1-6 carbon atoms, or mono or dialkyl aminoalkyl where eachalkyl is a straight or branched chain alkyl having 1-6 carbon atoms; or

vii) COR₇ or SO₂ R₇ where

R₇ is straight or branched chain lower alkyl having 1-6 carbon atoms,phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 4(5)-imidazolyl, or2-pyrimidinyl; or

R₇ is phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or4(5)-imidazolyl, or 2-pyrimidinyl each of which may be mono ordisubstituted with halogen, lower alkyl having 1-6 carbon atoms,straight or branched alkoxy having 1-6 carbon atoms, or alkoxyalkylwhere the alkoxy portion is straight or branched chain alkoxy having 1-6carbon atoms and the alkyl portion is straight or branched chain alkylhaving 1-6 carbon atoms; and

n is 0, 1, or 2.

These compounds, or prodrugs thereof, are highly selective agonists,antagonists, or inverse agonists at a modulatory site on one or moresubtypes of the brain GABAa receptor and are useful in the diagnosis andtreatment of anxiety, sleep, and seizure disorders, overdose withbenzodiazepine drugs, and enhancement of memory.

BRIEF DESCRIPTION OF THE DRAWING

FIGS. 1A-H shows representative examples of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed by the instant invention can bedescribed by the following general formula I: ##STR12## and thepharmaceutically acceptable non-toxic salts thereof wherein

Z is H₂, oxygen or sulfur;

R₁ and R₂ are hydrogen or straight chain or branched lower alkyl having1-6 carbon atoms;

X is ##STR13## with the proviso that when X is ##STR14## T is oxygen orsulfur, and when X is ##STR15## R₃ is hydrogen, halogen, aryloxy, alkoxyhaving 1-6 carbon atoms or OCOR₅ where R₅ is hydrogen, straight orbranched chain alkyl having 1-6 carbon atoms, alkoxy having 1-6 carbonatoms, or dialkylamino where each alkyl has 1-6 carbon atoms, and R₄ isH, lower alkyl having 1-6 carbon atoms or COR₆ where R₆ is hydrogen,straight or branched chain alkyl having 1-6 carbon atoms, alkoxy having1-6 carbon atoms or dialkylamino where each alkyl has 1-6 carbon atoms;

W is phenyl, 2- or 3-thienyl or 2-, 3-, or 4-pyridyl; or phenyl, 2- or3-thienyl or 2-, 3-, or 4-pyridyl, each of which is mono ordisubstituted with halogen, lower alkyl, or straight or branched chainlower alkoxy having 1-6 carbon atoms;

Y is

i) hydrogen, phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or4(5)-imidazolyl, 2-pyrimidinyl, or 1-indanyl;

ii) phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 4(5)-imidazolyl,or 2-pyrimidinyl, each of which is mono or disubstituted with halogen,lower alkyl having 1-6 carbon atoms, lower alkoxy having 1-6 carbonatoms, or alkoxylalkyl where the alkoxy portion is straight or branchedchain alkoxy having 1-6 carbon atoms and the alkyl portion is straightor branched chain alkyl having 1-6 carbon atoms;

iii) straight or branched chain alkyl having 1-6 carbon atoms;

iv) straight or branched chain alkyl having 1-6 carbon atoms, whereineach alkyl is substituted with the groups of ii;

v) cycloalkyl having 3-10 carbon atoms, cycloalkyl alkyl where thecycloalkyl portion has 3-7 carbon atoms and the alkyl portion has 1-6carbon atoms;

vi) aminoalkyl where the alkyl portion is straight or branched chainalkyl having 1-6 carbon atoms, or mono or dialkyl aminoalkyl where eachalkyl is a straight or branched chain alkyl having 1-6 carbon atoms; or

vii) COR₇ or SO₂ R₇ where

R₇ is straight or branched chain lower alkyl having 1-6 carbon atoms,phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 4(5)-imidazolyl, or2-pyrimidinyl; or

R₇ is phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or4(5)-imidazolyl, or 2-pyrimidinyl each of which may be mono ordisubstituted with halogen, lower alkyl having 1-6 carbon atoms,straight or branched alkoxy having 1-6 carbon atoms, or alkoxyalkylwhere the alkoxy portion is straight or branched chain alkoxy having 1-6carbon atoms and the alkyl portion is straight or branched chain alkylhaving 1-6 carbon atoms; and

n is 0, 1, or 2.

The invention also encompasses compounds of formula II: ##STR16## andthe pharmaceutically acceptable non-toxic salts thereof wherein

R₁ and R₂ are hydrogen or straight chain lower alkyl having 1-6 carbonatoms;

R₃ is hydrogen, halogen, aryloxy, alkoxy having 1-6 carbon atoms, orOCOR₅ where R₅ is hydrogen, straight or branched chain alkyl having 1-6carbon atoms, alkoxy having 1-6 carbon atoms, or dialkylamino where eachalkyl has 1-6 carbon atoms;

W is phenyl or phenyl monosubstituted with chlorine or fluorine; and

Y is hydrogen, lower alkyl having 1-6 carbon atoms, alkanoyl having 1-6carbon atoms, carboalkoxy having 1-6 alkyl carbon atoms, carbobenzyloxy,and pyridyl alkyl wherein the alkyl portion has 1-6 carbon atoms; or

phenylalkyl or thienylalkyl, where the phenyl or thienyl portion issubstituted with one or two chlorine or bromine atoms and the alkylportion has 1-3 alkyl carbon atoms.

The invention also encompassses compounds of formula III: ##STR17## andthe pharmaceutically acceptable non-toxic salts thereof wherein

T is oxygen or sulfur;

R₁ and R₂ are hydrogen or straight chain lower alkyl having 1-6 carbonatoms;

R₄ is hydrogen, lower alkyl, or COR₅ where R₅ is hydrogen, straight orbranched chain alkyl having 1-6 carbon atoms, alkoxy having 1-6 carbonatoms, or dialkylamino where each alkyl has 1-6 carbon atoms;

W is phenyl or phenyl monosubstituted with chlorine or fluorine; and

Y is

hydrogen, lower alkyl having 1-6 carbon atoms, alkanoyl having 1-6carbon atoms, carboalkoxy having 1-6 alkyl carbon atoms, carbobenzyloxy,and pyridyl alkyl wherein the alkyl portion has 1-6 carbon atoms; or

phenylalkyl or thienylalkyl, where the phenyl or thienyl portion issubstituted with one or two chlorine or bromine atoms and the alkylportion has 1-3 alkyl carbon atoms.

The invention also encompassses compounds of formula IV: ##STR18## andthe pharmaceutically acceptable non-toxic salts thereof wherein

R₁ and R₂ are hydrogen or straight chain lower alkyl having 1-6 carbonatoms;

R₄ is hydrogen, lower alkyl or COR₅ where R₅ is hydrogen, straight orbranched chain alkyl having 1-6 carbon atoms, alkoxy having 1-6 carbonatoms or dialkylamino where each alkyl has 1-6 carbon atoms;

W is phenyl or phenyl monosubstituted with chlorine or fluorine; and

Y is hydrogen, lower alkyl having 1-6 carbon atoms, alkanoyl having 1-6carbon atoms, carboalkoxy having 1-6 alkyl carbon atoms, carbobenzyloxy,and pyridyl alkyl wherein the alkyl portion has 1-6 carbon atoms; orphenylalkyl or thienylalkyl, where the phenyl or thienyl portion issubstituted with one or two chlorine or bromine atoms and the alkylportion has 1-3 alkyl carbon atoms.

These compounds arc highly selective agonists, antagonists, or inverseagonists at a modulatory site on one or more subtypes of the brain GABAareceptor, or prodrugs thereof, and arc useful in the diagnosis andtreatment of anxiety, sleep, and seizure disorders, overdose withbenzodiazepine drugs, and enhancement of memory.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluene sulfonic, hydroiodic, acetic and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in FIG. Iand their pharmaceutically acceptable salts.

The pharmaceutical utility of compounds of this invention are indicatedby the following assay for GABAa receptor activity.

Assays are carried out as described in Thomas and Tallman (J. Bio. Chem.156: 9838-9842, J. Neurosci. 3: 433-440, 1983). Rat conical tissue isdissected and homogenized in 25 volumes (w/v) of 0.05M Tris HCl buffer(pH 7.4 at 4° C.). The tissue homogenate is centrifuged in the cold (4°)at 20,000× g for 20'. The supernatant is decanted and the pellet isrehomogenized in the same volume of buffer and again centrifuged at20,000× g. The supernatant is decanted and the pellet is frozen at -20°C. overnight. The pellet is then thawed and rehomogenized in 25 volume(original wt/vol) of buffer and the procedure is carried out twice. Thepellet is finally resuspended in 50 volumes (w/vol of 0.05M Tris HClbuffer (pH 7.4 at 40° C.).

Incubations contain 100 μl of tissue homogenate 100 μl of radioligand0.5 nM (³ H-RO15-1788 specific activity 80 Ci/mmol), drug or blocker andbuffer to a total volume of 500 μl. Incubations are carried for 30 minat 4° C. then are rapidly filtered through GFB filters to separate freeand bound ligand. Filters are washed twice with fresh 0.05M Tris HClbuffer (pH 7.4 at 4° C.) and counted in a liquid scintillation counter.1.0 μM diazepam is added to some tubes to determine nonspecific binding.Data are collected in triplicate determinations, averaged and %inhibition of total specific binding is calculated. Total SpecificBinding=Total-Nonspecific. In some cases, the amounts of unlabeled drugsis varied and total displacement curves of binding are carried out. Dataare convened to a form for the calculation of IC₅₀ and Hill Coefficient(nH).

Data for representative compounds of this invention are listed in TableI.

                  TABLE I                                                         ______________________________________                                        Compound Number.sup.1                                                                          IC.sub.50 (μM)                                            ______________________________________                                         1               0.500                                                        13               0.0024                                                       14               0.100                                                        21               0.0048                                                       22               0.0038                                                       36               0.010                                                        44               0.010                                                        49               0.030                                                        ______________________________________                                         .sup.1 Compound numbers relate to compounds shown in FIG. I.             

Compounds 13, 21 and 22 are particularly preferred embodiments of thepresent invention because of their potency in binding to the GABAareceptor.

The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carder. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, locithin, andesters or partial esters derived from fatty acids and boxitel,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono-or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The mount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

Compounds of the present invention are prepared according to Schemes Ior II: ##STR19## Where:

R₁ and R₂ are hydrogen or straight chain or branched lower alkyl having1-6 carbon atoms;

R₃ is hydrogen, halogen, aryloxy, alkoxy having 1-6 carbon atoms orOCOR₅ where R₅ is hydrogen, straight or branched chain alkyl having 1-6carbon atoms, alkoxy having 1-6 carbon atoms or dialkylamino where eachalkyl has 1-6 carbon atoms;

R₄ is Lower alkyl or COR₅ where R₅ is hydrogen, straight or branchedchain alkyl having 1-6 carbon atoms, aryl, alkoxy having 1-6 carbonatoms or dialkylamino having 1-6 carbon atoms:

W is

phenyl, 2- or 3-thienyl or 2-, 3-, or 4-pyridyl;

or phenyl, 2- or 3-thienyl or 2-, 3-, or 4-pyridyl, each of which ismono or disubstituted with halogen, lower alkyl, or straight or branchedchain lower alkoxy having 1-6 carbon atoms;

Y is

i) hydrogen, phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or4(5)-imidazolyl, 2-pyrimidinyl, or 1-indanyl;

ii) phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 4(5)-imidazolyl,or 2-pyrimidinyl, each of which is mono or disubstituted with halogen,lower alkyl having 1-6 carbon atoms, lower alkoxy having 1-6 carbonatoms, or alkoxylalkyl where the alkoxy portion is straight or branchedchain alkoxy having 1-6 carbon atoms and the alkyl portion is straightor branched chain alkyl having 1-6 carbon atoms;

iii) straight or branched chain alkyl having 1-6 carbon atoms;

iv) straight or branched chain alkyl having 1-6 carbon atoms, whereineach alkyl is substituted with the groups of ii;

v) cycloalkyl having 3-10 carbon atoms, cycloalkyl alkyl where thecycloalkyl portion has 3-7 carbon atoms and the alkyl portion has 1-6carbon atoms;

vi) aminoalkyl where the alkyl portion is straight or branched chainalkyl having 1-6 carbon atoms, or mono or dialkyl aminoalkyl where eachalkyl is a straight or branched chain alkyl having 1-6 carbon atoms; or

vii) COR₇ or SO₂ R₇ where

R₇ is straight or branched chain lower alkyl having 1-6 carbon atoms,phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 4(5)-imidazolyl, or2-pyrimidinyl; or

R₇ is phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or4(5)-imidazolyl, or 2-pyrimidinyl each of which may be mono ordisubstituted with halogen, lower alkyl having 1-6 carbon atoms,straight or branched alkoxy having 1-6 carbon atoms, or alkoxyalkylwhere the alkoxy portion is straight or branched chain alkoxy having 1-6carbon atoms and the alkyl portion is straight or branched chain alkylhaving 1-6 carbon atoms; and

n is 0, 1, or 2.

Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present invention, as demonstrated by the followingexamples.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them.

EXAMPLE I ##STR20##

To a stirred suspension of 4-Amino-3-cyano-1,2,5,6-tetrahydropyridine(prepared according to a the procedure described by Taub et al., 1967,J. Chem. Soc. C: 1558) (95.51 g, 775 mmol) in pyridine (500 mL), benzoicanhydride (274 g, 1.20 mol) was added in portions over 1-2 hours. Afterstirring an additional 30 minutes, the precipitate was collected, washedfirst with toluene, then ether, and subsequently allowed to dry toafford 1-benzoyl-4-amino-3-cyano-1,2,5,6-tetrahydropyridine as a whitesolid, m.p. 178°-181° C.

EXAMPLE II ##STR21##

A slurry of 1-benzoyl-4-amino-3-cyano-1,2,5,6-tetrahydropyridine (35.23g, 155 mmol) and urea (46.55 g, 775 mmol) in 2-(2-ethoxyethoxy)ethanol(75 mL) was gradually heated to about 205° C., and maintained at 205° C.for 90 minutes. Heating was ceased and hot water was carefully addedwhile shaking the mixture. The mixture was vacuum filtered to collectthe precipitate while hot. The precipitate was washed with hot wateruntil the filtrate was colorless. The precipitate was then washed withethanol until the filtrate was colorless, and then finally with ethylacetate and allowed to dry to yield6-benzoyl-4-amino-6,7,8,9-tetrahydro-pyrido[3,4-e]pyrimidin-2-one as alight yellow solid.

EXAMPLE III ##STR22##

A mixture of6-benzoyl-4-amino-6,7,8,9-tetrahydro-pyrido[3,4-e]pyrimidin-2-one (1 g,3.7 mmol) and 1-bromo-2'-fluoroacetophenone (0.74 g, 3.7 mmol) in 8 mLof dimethylformamide (DMF) was heated at about 150° C. for 45 minutes.The reaction mixture was poured into ice water and the precipitatecollected to give9-Benzoyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 1). Later, a second crop of precipitate was collected as acream-colored solid. m.p. 269°-271° C. (d).

EXAMPLE IV

The following compounds were prepared according to the proceduresdescribed in Examples I-III:

(a)9-Benzoyl-2-(3-chlorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 2), m.p. 250°-253° C. (d).

(b)9-Benzoyl-2-(3-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 3).

(c) 9-Benzoyl-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 4).

(d)9-Benzoyl-2-(4-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 5), m.p. 295°-300° C.

(e)9-Benzoyl-2-(4-methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 6).

EXAMPLE V ##STR23##

To a solution of9-Benzoyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(435 mg, 1.1 mmol) in ethanol (5 mL) was added 5 mL of 50% aqueoussodium hydroxide. The mixture was refluxed for about 1 hour, and thenpoured into saturated aqueous ammonium chloride and extracted twice with10% methanol/ethyl acetate. The combined organic layers were dried overmagnesium sulfate, filtered, concentrated, and triturated withmethanol/ether to give2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin 5(6H)-one(Compound 7), m.p. >310° C.

EXAMPLE VI

The following compounds were prepared according to the proceduredescribed in Example V:

(a) 2-(2- Chlorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compund 8), m.p. 320°-322° C.

b) 2-(3-Fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 9).

(c) 2-Phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 10), m.p. >310° C.

(d)2-(4-Fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 11).

(e)2-(4-Methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 12).

(f)2-(3-Chlorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compund 57), m.p. 320°-322° C.

EXAMPLE VII ##STR24##

2-Fluorobenzyl bromide (54 uL, 0.45 mmol) was added to a solution of2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (128 mg, 0.45 mmol) and triethylamine (76 uL, 0.54mmol) in DMF (1 mL) at room temperature. The reaction mixture wasstirred for 45 minutes, and then concentrated. Aqueous sodiumbicarbonate was added, the aqueous layer extracted twice with 10%methanol/ethyl acetate, and the combined organic layers dried overmagnesium sulfate, filtered, concentrated, and triturated withmethanol/ether to give9-(2-Fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 13) as an off-white solid, m.p. 270°-273°C. Treatment with ethanolic HCl affords the corresponding HCl salt.

EXAMPLE VIII

The following compounds were prepared according to the proceduredescribed in Example VII:

(a)9-Benzyl-2-(3-chlorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 14), as an off-white solid, m.p. 255°-256°C.

(b)9-Benzyl-2-(3-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 15), as a pale yellow solid, m.p.273°-274° C.

(c)9-Benzyl-2-(4-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 16), as an off white solid, m.p. 272°-274° C.

(d)9-Benzyl-2-(4-methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 17).

(e)9-Benzyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 18), as an off white solid, m.p. 281°-282°C.

(f)9-Benzyl-2-phenyl-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 19).

(g)9-(2-pyrimidinyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 20), as an off white solid, m.p. >270° C.

(h)±9-(α-Methylbenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 21), as an off white solid. m.p. 265°-266°C.

(i)9-(4-Fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 22), as an off white solid, m.p. >270° C.

(j)9-(4-Methoxybenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 23), as a tan solid. m.p. >270° C.

(k)9-(4-Methylbenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 24), as an off white solid, m.p. 265°-267°C.

(l)9-(3,4-Difluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 25), as an off white solid, m.p. 271°-273° C.

(m)9-(2,4-Difluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 26), as an off white solid. m.p. 270°-272° C.

(n)±9-(4-Fluoro-α-Methylbenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-onemono hydrochloride (Compound 27), as an off white solid, m.p. 278°-280°C.

(o)9-(3-Fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 28), as an off white solid, m.p. 268°-269° C.

(p)±9-(3-Fluoro-α-methylbenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 29), as an off white solid, m.p. 262°-264° C.

(q)9-(2-methylbenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 30), as a white solid, m.p. 287°-289° C.

(r)±9-(2-Fluoro-α-methylbenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 31), as an off white solid, m.p. 272°-274° C.

(s)±9-(1-indanyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 32).

(t)9-(2-propyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 33).

(u)9-cyclohexylmethyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 34), as a white solid. m.p. 265°-267° C.

(v)±9-benzyl-2-(2-fluorophenyl)-8-methyl-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 35).

EXAMPLE IX ##STR25##

Propionyl chloride (39 uL, 0.4 mmol) was added to a solution of2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (124 mg, 0.4 mmol) and triethylamine (74 uL, 0.5mmol) in DMF (2 mL) at room temperature. The reaction mixture wasstirred for 50 minutes, and then poured into ice water. The precipitatewas collected, washed with water and 95% ethanol, and dried to yield9-propionyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 36) as a white solid, m.p. >310° C.

EXAMPLE X

The following compounds were prepared according to the proceduredescribed in Example IX:

(a)9-Butyryl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 37), as a white solid, m.p. 309°-311° C.

(b)9-Hexanoyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one, (Compound 38), as a white solid, m.p. 295°-297° C.

(c)9-Phenylacetyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 39), as an off-white solid, m.p. 307°-309°C.

(d)9-Acetyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 40), as an off-white solid, m.p. >315° C.

(e)9-Nicotinoyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 41), as an off-white solid, m.p. 280°-282° C.

(f)9-Isonicotinoyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 42), as an off-white solid, m.p. >300° C.

(g)9-Picolinoyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 43), as an off-white solid, m.p. 287°-290° C.

EXAMPLE XI ##STR26##

Benzyl chloroformate (57 uL, 0.4 mmol) was added to a solution of2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (124 mg, 0.4 mmol) and triethylamine (74 uL, 0.5mmol) in DMF (1 mL) at room temperature. The reaction mixture wasstirred for 1 hour, then poured into ice water. The precipitate wascollected, washed with 95% ethanol and ether, and subsequently dried togive9-Carbobenzyloxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 44). Recrystallization from aqueous ethanol afforded Compound41 as an off-white solid. m.p. 250° C. (d).

EXAMPLE XII

The following compounds were prepared according to the proceduredescribed in Example XI:

(a)9-Carboethoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 45) as a white solid, m.p. 297°-299° C(d).

(b)9-Carbobutoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 46) as a white solid, m.p. 268°-269° C.

(c)9-Phenylsulfonyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 47).

EXAMPLE XIII ##STR27##

To2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(171 mg, 0.6 mmol) in pH4-5 HCL-methanol (6 mL) at room temperature wasadded n -butyraldehyde (53 uL, 0.6 mmol) and sodium cyanoborohydride (38mg, 0.6 mmol). After the reaction mixture was stirred for 6 hours,concentrated HCl was added until the mixture became homogenous. Themixture was then diluted with water (5 mL) and extracted twice withether. The aqueous layer was made alkaline with aqueous ammoniumhydroxide, saturated with sodium chloride, and extracted twice with 10%methanol/ethyl acetate. The combined organic layers were dried overmagnesium sulfate, filtered and concentrated to give9-n-Butyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 48). Recrystallization from aqueousethanol gave a white fluffy solid, m.p. 251°-253° C. (d).

EXAMPLE XIV

The following compounds were prepared according to the proceduredescribed in Example XIII:

(a)9-Methyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 49) as a yellow solid, m.p. 290°-291° C.

(b)9-(2-Phenylethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 50) as a cream-colored solid, m.p. 264°-266° C.

(c)9-(3-Phenylpropyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 51) as a white fluffy solid, m.p. 244°-245° C.

EXAMPLE XV ##STR28##

A mixture of9-(Nicotinoyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(128 mg, 0.33 mmol), methylene chloride (3 mL) and 1M borane in THF (3.3mL) was stirred at room temperature for 16 h. The reaction mixture wascarefully acidified with 5 mL of 6N HCl and heated at reflux for 15 min.The reaction mixture was made alkaline with 10% NaOH and the product wasextracted with 10% methanol in ethyl acetate. After drying overmagnesium sulfate the solvent was removed in vacuo to afford a yellowsolid which was recrystallized from ethanol to afford9-(3-Pyridylmethyl)-2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 52) as a pale yellow solid, m.p. 290°-292° C.

EXAMPLE XVI

The following compounds were prepared according to the proceduredescribed in Example XV:

(a)9-(2-Pyridylmethyl)-2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 53).

(b)9-(4-Pyridylmethyl)-2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 54), as an off white solid. m.p. 293°-294° C.

EXAMPLE XVII ##STR29##

A mixture of9-(2-fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(392 mg, 1 mmol) and 50% sodium hydride (144 mg, 3 mmol) in DMF (5 mL)was stirred at room temperature for 15 min. Acetyl chloride (1 mL) wasadded and stirring was continued for 30 min. The reaction was dilutedwith ethyl acetate and washed with water. After drying over magnesiumsulfate, the solvent was removed in vacuo and the residue was subjectedto flash chromatography on silica gel with 30% ethyl acetate in hexaneas the eluent to afford6-acetyl-9-(2-fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(compound 55) and5-acetoxy-9-(2-fluorobenzyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2c]pyrido[3,4-e]pyrimidine(compound 56) as white solids.

EXAMPLE XVIII

The following additional examples were prepared according to theprocedure described in Example VII:

(a)9-Benzyl-2-(4-chlorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 58).

(b)9-Ethyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 59), as an off-white solid, m.p. 266°-268° C.

(c)9-Allyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 60), as an off-white solid. m.p. 270°-273°C.

(d)9-Cyclpropylmethyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 61), as an off-white solid. m.p. >275° C.

(e)9-(4(5)-Imidazoylmethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 62), as an off-white solid. m.p. 275°-277° C.

(f)9-Benzyl-2-(2,4-difluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 63), as an off-white solid, m.p. 275°-277° C.

(g)9-Benzyl-2-(2-fluoro-4-methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 64), as an off-white solid, m.p. 257°-261°C.

(h)9-(2-Thienylmethyl)-2-(fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 65), as an off-white solid. m.p. 270°-271° C.

(i)9-(2-Imidazoylmethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 66), as an off-white solid. m.p. 210°-215°C.

(k)9-Methyl-2-(4-methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 67), as an off-white solid, m.p. 264°-267°C.

(l)9-Benzyl-2-(4-methylphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 68), as an off-white solid, m.p. 255°-258°C.

(m)9-Methyl-2-(2-fluoro-4-methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 69).

(n)9-Benzyl-2-(3,4-difluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 70), as an off-white solid, m.p. 268°-271°C.

(o)9-Benzyl-2-(3-methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 71), as an off-white solid, m.p. 269°-271° C.

(p)9-Benzyl-2-(2-thienyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 72), as an off-white solid; m.p. 271°-274° C.

(q)9-Benzyl-2-(2-methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 73).

(r)9-Benzyl-2-(2,5-difluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one(Compound 74).

What is claimed is:
 1. A compound of the formula: ##STR30## or thepharmaceutically acceptable non-toxic salts thereof wherein Z is H₂,oxygen or sulfur;R₁ and R₂ are hydrogen or straight chain or branchedlower alkyl having 1-6 carbon atoms; X is ##STR31## with the provisothat when X is ##STR32## T is oxygen or sulfur, and when X is ##STR33##R₃ is hydrogen, halogen, arloxy, alkoxy having 1-6 carbon atoms or OCOR₅where R₅ is hydrogen, straight or branched chain alkyl having 1-6 carbonatoms, alkoxy having 1-6 carbon atoms, or dialkylamino where each alkylhas 1-6 carbon atoms, and R₄ is H, lower alkyl having 1-6 carbon atomsor COR₆ where R₆ is hydrogen, straight or branched chain alkyl having1-6 carbon atoms, alkoxy having 1-6 carbon atoms or dialkylamino whereeach alkyl has 1-6 carbon atoms; W isphenyl, 2- or 3-thienyl or 2-, 3-,or 4-pyridyl; or phenyl. 2- or 3-thienyl or 2-, 3-, or 4-pyridyl, eachof which is mono or disubstituted with halogen, lower alkyl, or straightor branched chain lower alkoxy having 1-6 carbon atoms; Y isi) hydrogen,phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or 4(5)-imidazolyl,2-pyrimidinyl, or 1-indanyl; ii) phenyl, 2- or 3-thienyl, 2-, 3- or4-pyridyl, 2- or 4(5)-imidazolyl, or 2-pyrimidinyl, each of which ismono or disubstituted with halogen, lower alkyl having 1-6 carbon atoms,lower alkoxy having 1-6 carbon atoms, or alkoxylalkyl where the alkoxyportion is straight or branched chain alkoxy having 1-6 carbon atoms andthe alkyl portion is straight or branched chain alkyl having 1-6 carbonatoms; iii) straight or branched chain alkyl having 1-6 carbon atoms;iv) straight or branched chain alkyl having 1-6 carbon atoms, whereineach alkyl is substituted with the groups of ii; v) cycloalkyl having3-10 carbon atoms, cycloalkyl alkyl where the cycloalkyl portion has 3-7carbon atoms and the alkyl portion has 1-6 carbon atoms; vi) aminoalkylwhere the alkyl portion is straight or branched chain alkyl having 1-6carbon atoms, or mono or dialkyl aminoalkyl where each alkyl is astraight or branched chain alkyl having 1-6 carbon atoms; or vii) COR₇or SO₂ R₇ whereR₇ is straight or branched chain lower alkyl having 1-6carbon atoms, phenyl, 2- or 3-thienyl, 2-, 3- or 4-pyridyl, 2- or4(5)-imidazolyl, or 2-pyrimidinyl; or R₇ is phenyl, 2- or 3-thienyl, 2-,3- or 4-pyridyl, 2- or 4(5)-imidazolyl, or 2-pyrimidinyl each of whichmay be mono or disubstituted with halogen, lower alkyl having 1-6 carbonatoms, straight or branched alkoxy having 1-6 carbon atoms, oralkoxyalkyl where the alkoxy portion is straight or branched chainalkoxy having 1-6 carbon atoms and the alkyl portion is straight orbranched chain alkyl having 1-6 carbon atoms; and n is 0, 1, or
 2. 2. Acompound of the formula: ##STR34## or the pharmaceutically acceptablenon-toxic salts thereof wherein R₁ and R₂ are hydrogen or straight chainlower alkyl having 1-6 carbon atoms;R₃ is hydrogen, halogen, phenoxy,alkoxy having 1-6 carbon atoms, or OCOR₅ where R₅ is hydrogen, straightor branched chain alkyl having 1-6 carbon atoms, alkoxy having 1-6carbon atoms, or dialkylamino where each alkyl has 1-6 carbon atoms; Wis phenyl or phenyl monosubstituted with chlorine or fluorine; and Yishydrogen, lower alkyl having 1-6 carbon atoms, alkanoyl having 1-6carbon atoms, carboalkoxy having 1-6 alkyl carbon atoms, carbobenzyloxy,and pyridyl alkyl wherein the alkyl portion has 1-6 carbon atoms; orphenylalkyl or thienylalkyl, where the phenyl or thienyl portion issubstituted with one or two chlorine or bromine atoms and the alkylportion has 1-3 alkyl carbon atoms.
 3. A compound according to claim 1of the formula: ##STR35## or the pharmaceutically acceptable non-toxicsalts thereof wherein T is oxygen or sulfur;R₁ and R₂ are hydrogen orstraight chain lower alkyl having 1-6 carbon atoms; R₄ is hydrogen,lower alkyl, or COR₅ where R₅ is hydrogen, straight or branched chainalkyl having 1-6 carbon atoms, alkoxy having 1-6 carbon atoms, ordialkylamino where each alkyl has 1-6 carbon atoms; W is phenyl orphenyl monosubstituted with chlorine or fluorine; and Y ishydrogen,lower alkyl having 1-6 carbon atoms, alkanoyl having 1-6 carbon atoms,carboalkoxy having 1-6 alkyl carbon atoms, carbobenzyloxy, and pyridylalkyl wherein the alkyl portion has 1-6 carbon atoms; or phenylalkyl orthienylalkyl, where the phenyl or thienyl portion is substituted withone or two chlorine or bromine atoms and the alkyl portion has 1-3 alkylcarbon atoms.
 4. A compound according to claim 1 of the formula:##STR36## or the pharmaceutically acceptable non-toxic salts thereofwherein R₁ and R₂ are hydrogen or straight chain lower alkyl having 1-6carbon atoms;R₄ is hydrogen, lower alkyl or COR₅ where R₅ is hydrogen,straight or branched chain alkyl having 1-6 carbon atoms, alkoxy having1-6 carbon atoms or dialkylamino where each alkyl has 1-6 carbon atoms;W is phenyl or phenyl monosubstituted with chlorine or fluorine; and Yishydrogen, lower alkyl having 1-6 carbon atoms, alkanoyl having 1-6carbon atoms, carboalkoxy having 1-6 alkyl carbon atoms, carbobenzyloxy,and pyridyl alkyl wherein the alkyl portion has 1-6 carbon atoms; orphenylalkyl or thienylalkyl, where the phenyl or thienyl portion issubstituted with one or two chlorine or bromine atoms and the alkylportion has 1-3 alkyl carbon atoms.
 5. A compound according to claim 1,wherein X is ##STR37## and R₂ are H and n is
 1. 6. A compound accordingto claim 2, wherein W is phenyl monosubstituted with chlorine orfluorine.
 7. A compound according to claim 3, wherein W is phenylmonosubstituted with fluorine.
 8. A compound according to claim 4,wherein Y is 3-phenylpropyl.
 9. A compound according to claim 4, whereinY is acetyl.
 10. A compound according to claim 4, wherein Y iscarboethoxy.
 11. A compound according to claim 4, wherein Y is butyl.12. A compound according to claim 4, wherein Y is benzyl.
 13. A compoundaccording to claim 4, wherein Y is hexanoyl.
 14. A compound according toclaim 4, wherein Y is methyl.
 15. A compound according to claim 4,wherein Y is carbobenzyloxy.
 16. A compound according to claim 4,wherein Y is hydrogen.
 17. A compound according to claim 1, which is2-(3-Chlorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidine.18. A compound according to claim 1, which is9-Benzyl-2-(4-chlorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.19. A compound according to claim 1, which is9-Ethyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.20. A compound according to claim 1, which is9-Allyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.21. A compound according to claim 1, which is9-Cyclopropylmethyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.22. A compound according to claim 1, which is9-(4(5)-Imidazoylmethyl)-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5-(6H)-one.23. A compound according to claim 1, which is9-Benzyl-2-(2,4-difluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.24. A compound according to claim 1, which is9-Benzyl-2-(2-fluoro-4-methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-pyrido[3,4-e]pyrimidin-5(6H)-one.25. A compound according to claim 1, which is9-(2-Thienylmethyl)-2-(fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.26. A compound according to claim 1, which is9-(2-Imidazoylmethyl)-2-2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5-(6H)-one.
 27. A compound according to claim 1, which is9-Methyl-2-(4-methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.28. A compound according to claim 1, which is9-Benzyl-2-(4-methylphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.29. A compound according to claim 1, which is9-Methyl-2-(2-fluoro-4-methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.30. A compound according to claim 1, which is9-Benzyl-2-(3,4-difluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.31. A compound according to claim 1, which is9-Benzyl-2-(3-methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5-(6H)-one.32. A compound according to claim 1, which is9-Benzyl-2-(2-thienyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.33. A compound according to claim 1, which is9-Benzyl-2-(2-methoxyphenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.34. A compound according to claim 1, which is9-Benzyl-2-(2,5-difluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one.